The Copenhagen Analgesic Study

NCT04369222 | Completed DMC

• 1 other identifier: COPANA5064
• Study Type: observational
• Target: 685
• Locations: 1 country
• Sites: 2

Brief Summary

Fundamental aspects of reproductive function are established in fetal life and there is a present increased awareness of the potential effects of fetal exposures on reproductive health of offspring. Experimental studies strongly suggest detrimental effects of prenatal exposure to mild analgesics such as acetaminophen (e.g. paracetamol) and non-steroidal anti-inflammatory drugs, NSAIDs (e.g. ibuprofen and acetylsalicylic acid) on male as well as female gonadal development. Declining fertility has become a growing problem in developing countries, potentially resulting in severe socioeconomic challenges, and fetal exposure of mild analgesics causes part of these alarming observations.This is the first prospective human study designed primarily to assess the effect of fetal exposure of mild analgesics on male and female reproductive function.

Conditions

Gonad Regulating Hormone Adverse Reaction; Analgesic Adverse Reaction

Outcome Measures

Primary Outcomes (5)

• Ovarian volume (female infants)

  Ovarian volumen, measured by abdominal ultrasound

  2.5 months old

• Ovarian follicle count (female infants)

  Ovarian follicle count, measured by abdominal ultrasound

  2.5 months old

• Blood sample (female infants)

  Serum metabolites Anti Müllarian Hormone (AMH)

  2.5 months old

• Testes volumen (male infants)

  Testes volumen, measured by ultrasound

  2.5 months old

• Blood sample (male infants)

  Serum metabolites testosterone, free testosterone.

  2.5 months old

Secondary Outcomes (43)

• Length (male and female infants)

  2.5 months old

• Weight (male and female infants)

  2.5 months old

• Head circumference (male and female infants)

  2.5 months old

• Abdominal circumference (male and female infants)

  2.5 months old

• Height (fathers)

  Gestational week 12

Study Arms (2)

Controls

Children born from mothers with no consumption of mild analgesics 3 months before or during pregnancy

Exposed

Children born from mothers with consumption of mild analgesics 3 months before or during pregnancy

Other: Observational

Interventions

Observational OTHER

Maternal consumption of mild analgesics

Also known as: Acetaminophen, Non steroidal antiinflammatory drugs, Acetyl salicylic acid

Exposed

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This study is a population based prospective cohort study of 600 families (healthy pregnant mothers, biological fathers and their healthy male/female offspring. Pregnant women, meeting the inclusion criteria, and the fathers-to-be followed at the Department of Obstetrics, Rigshospitalet will be invited to participate. There are two groups of participants in this study: 1. Healthy infants recruited specifically for this study 2. The parents, i.e. the mother and father, of the healthy infants The two groups will include the following numbers (approximately) of participants: 1. 600 healthy infants (based on expected son to daughter ratio of 105 to 100 in Denmark, we expect approximately equal distribution of boys and girl). 2. 600 mothers and 600 fathers of healthy infants

You may qualify if:

• Infants:
• Singleton pregnancies
• Term pregnancy (week 37+0 to 42+0)
• Parents:
• Maternal and paternal Caucasian origin
• Maternal pre-pregnancy BMI between 18 and 35 kg/m2

You may not qualify if:

• Infants:
• Fetal malformations or chromosomal disorders
• Parents:
• Serious maternal illness, including pre-existing maternal diabetes or thyroid gland diseases
• Gestational diabetes

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead

Study Sites (2)

Department of Growth and Reproduction, Rigshospitalet

Copenhagen, 2100, Denmark

Location

Department of Obstetrics and Section of fetal medicine, Rigshospitalet

Copenhagen, 2100, Denmark

Location

Related Publications (24)

• Dean A, van den Driesche S, Wang Y, McKinnell C, Macpherson S, Eddie SL, Kinnell H, Hurtado-Gonzalez P, Chambers TJ, Stevenson K, Wolfinger E, Hrabalkova L, Calarrao A, Bayne RA, Hagen CP, Mitchell RT, Anderson RA, Sharpe RM. Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences. Sci Rep. 2016 Jan 27;6:19789. doi: 10.1038/srep19789.

  PMID: 26813099 BACKGROUND

• Arendrup FS, Mazaud-Guittot S, Jegou B, Kristensen DM. EDC IMPACT: Is exposure during pregnancy to acetaminophen/paracetamol disrupting female reproductive development? Endocr Connect. 2018 Jan;7(1):149-158. doi: 10.1530/EC-17-0298. Epub 2018 Jan 5.

  PMID: 29305399 BACKGROUND

• Kristensen DM, Mazaud-Guittot S, Gaudriault P, Lesne L, Serrano T, Main KM, Jegou B. Analgesic use - prevalence, biomonitoring and endocrine and reproductive effects. Nat Rev Endocrinol. 2016 Jul;12(7):381-93. doi: 10.1038/nrendo.2016.55. Epub 2016 May 6.

  PMID: 27150289 BACKGROUND

• Kristensen DM, Hass U, Lesne L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, Boberg J, Petersen JH, Toppari J, Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main KM, Jegou B, Leffers H. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum Reprod. 2011 Jan;26(1):235-44. doi: 10.1093/humrep/deq323. Epub 2010 Nov 8.

  PMID: 21059752 BACKGROUND

• Holm JB, Mazaud-Guittot S, Danneskiold-Samsoe NB, Chalmey C, Jensen B, Norregard MM, Hansen CH, Styrishave B, Svingen T, Vinggaard AM, Koch HM, Bowles J, Koopman P, Jegou B, Kristiansen K, Kristensen DM. Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility. Toxicol Sci. 2016 Mar;150(1):178-89. doi: 10.1093/toxsci/kfv332. Epub 2016 Jan 5.

  PMID: 26732887 BACKGROUND

• BAKER TG. A QUANTITATIVE AND CYTOLOGICAL STUDY OF GERM CELLS IN HUMAN OVARIES. Proc R Soc Lond B Biol Sci. 1963 Oct 22;158:417-33. doi: 10.1098/rspb.1963.0055. No abstract available.

  PMID: 14070052 BACKGROUND

• Reel JR, Lawton AD, Lamb JC 4th. Reproductive toxicity evaluation of acetaminophen in Swiss CD-1 mice using a continuous breeding protocol. Fundam Appl Toxicol. 1992 Feb;18(2):233-9. doi: 10.1016/0272-0590(92)90051-i.

  PMID: 1601223 BACKGROUND

• Johansson HK, Jacobsen PR, Hass U, Svingen T, Vinggaard AM, Isling LK, Axelstad M, Christiansen S, Boberg J. Perinatal exposure to mixtures of endocrine disrupting chemicals reduces female rat follicle reserves and accelerates reproductive aging. Reprod Toxicol. 2016 Jun;61:186-94. doi: 10.1016/j.reprotox.2016.03.045. Epub 2016 Apr 2.

  PMID: 27049580 BACKGROUND

• Ersboll AS, Hedegaard M, Damm P, Johansen M, Tabor A, Hegaard HK. Changes in the pattern of paracetamol use in the periconception period in a Danish cohort. Acta Obstet Gynecol Scand. 2015 Aug;94(8):898-903. doi: 10.1111/aogs.12667. Epub 2015 May 29.

  PMID: 25939806 BACKGROUND

• Lind DV, Main KM, Kyhl HB, Kristensen DM, Toppari J, Andersen HR, Andersen MS, Skakkebaek NE, Jensen TK. Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons: a cohort study of 1027 mother-child pairs. Hum Reprod. 2017 Jan;32(1):223-231. doi: 10.1093/humrep/dew285. Epub 2016 Nov 16.

  PMID: 27852690 BACKGROUND

• Rebordosa C, Zelop CM, Kogevinas M, Sorensen HT, Olsen J. Use of acetaminophen during pregnancy and risk of preeclampsia, hypertensive and vascular disorders: a birth cohort study. J Matern Fetal Neonatal Med. 2010 May;23(5):371-8. doi: 10.3109/14767050903334877.

  PMID: 19929241 BACKGROUND

• Nitsche JF, Patil AS, Langman LJ, Penn HJ, Derleth D, Watson WJ, Brost BC. Transplacental Passage of Acetaminophen in Term Pregnancy. Am J Perinatol. 2017 May;34(6):541-543. doi: 10.1055/s-0036-1593845. Epub 2016 Nov 2.

  PMID: 27806383 BACKGROUND

• Myrskyla M, Kohler HP, Billari FC. Advances in development reverse fertility declines. Nature. 2009 Aug 6;460(7256):741-3. doi: 10.1038/nature08230.

  PMID: 19661915 BACKGROUND

• Tromp M, Ravelli AC, Reitsma JB, Bonsel GJ, Mol BW. Increasing maternal age at first pregnancy planning: health outcomes and associated costs. J Epidemiol Community Health. 2011 Dec;65(12):1083-90. doi: 10.1136/jech.2009.095422. Epub 2010 Aug 13.

  PMID: 20709858 BACKGROUND

• Gallavan RH Jr, Holson JF, Stump DG, Knapp JF, Reynolds VL. Interpreting the toxicologic significance of alterations in anogenital distance: potential for confounding effects of progeny body weights. Reprod Toxicol. 1999 Sep-Oct;13(5):383-90. doi: 10.1016/s0890-6238(99)00036-2.

  PMID: 10560587 BACKGROUND

• Juul A, Almstrup K, Andersson AM, Jensen TK, Jorgensen N, Main KM, Rajpert-De Meyts E, Toppari J, Skakkebaek NE. Possible fetal determinants of male infertility. Nat Rev Endocrinol. 2014 Sep;10(9):553-62. doi: 10.1038/nrendo.2014.97. Epub 2014 Jun 17.

  PMID: 24935122 BACKGROUND

• Dean A, Sharpe RM. Clinical review: Anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J Clin Endocrinol Metab. 2013 Jun;98(6):2230-8. doi: 10.1210/jc.2012-4057. Epub 2013 Apr 8.

  PMID: 23569219 BACKGROUND

• Leverrier-Penna S, Mitchell RT, Becker E, Lecante L, Ben Maamar M, Homer N, Lavoue V, Kristensen DM, Dejucq-Rainsford N, Jegou B, Mazaud-Guittot S. Ibuprofen is deleterious for the development of first trimester human fetal ovary ex vivo. Hum Reprod. 2018 Mar 1;33(3):482-493. doi: 10.1093/humrep/dex383.

  PMID: 29408962 BACKGROUND

• Snijder CA, Kortenkamp A, Steegers EA, Jaddoe VW, Hofman A, Hass U, Burdorf A. Intrauterine exposure to mild analgesics during pregnancy and the occurrence of cryptorchidism and hypospadia in the offspring: the Generation R Study. Hum Reprod. 2012 Apr;27(4):1191-201. doi: 10.1093/humrep/der474. Epub 2012 Feb 2.

  PMID: 22301570 BACKGROUND

• Gilboa Y, Perlman S, Kivilevitch Z, Messing B, Achiron R. Prenatal Anogenital Distance Is Shorter in Fetuses With Hypospadias. J Ultrasound Med. 2017 Jan;36(1):175-182. doi: 10.7863/ultra.16.01006. Epub 2016 Nov 28.

  PMID: 27925677 BACKGROUND

• Mendiola J, Stahlhut RW, Jorgensen N, Liu F, Swan SH. Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York. Environ Health Perspect. 2011 Jul;119(7):958-63. doi: 10.1289/ehp.1103421. Epub 2011 Mar 4.

  PMID: 21377950 BACKGROUND

• Kuiri-Hanninen T, Sankilampi U, Dunkel L. Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Horm Res Paediatr. 2014;82(2):73-80. doi: 10.1159/000362414. Epub 2014 Jul 5.

  PMID: 25012863 BACKGROUND

• Lanciotti L, Cofini M, Leonardi A, Penta L, Esposito S. Up-To-Date Review About Minipuberty and Overview on Hypothalamic-Pituitary-Gonadal Axis Activation in Fetal and Neonatal Life. Front Endocrinol (Lausanne). 2018 Jul 23;9:410. doi: 10.3389/fendo.2018.00410. eCollection 2018.

  PMID: 30093882 BACKGROUND

• Fischer MB, Mola G, Rom AL, Frederiksen H, Johannsen TH, Sundberg K, Hegaard HK, Juul A, Hagen CP. Ovarian and Uterine Morphology in Minipuberty: Associations With Reproductive Hormones: a COPANA Study of 302 Girls. J Clin Endocrinol Metab. 2025 Mar 17;110(4):1015-1022. doi: 10.1210/clinem/dgae678.

  PMID: 39329336 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

DNA EDTA-Blood Serum

MeSH Terms

Interventions

Watchful Waiting; Acetaminophen

Intervention Hierarchy (Ancestors)

Outcome Assessment, Health Care; Outcome and Process Assessment, Health Care; Quality of Health Care; Health Services Administration; Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Study Officials

• Anders Juul, Professor

  Department of Growth and Reproduction, Rigshospitalet

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 20, 2020
• First Posted: April 30, 2020
• Study Start: March 1, 2020
• Primary Completion: November 30, 2022
• Study Completion: November 30, 2022
• Last Updated: July 10, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

DK (2)